Plasma samples of 42 patients with NSCLC were collected between 20. Here, we have studied a commercial NGS panel using molecular tagging of the DNA alleles present in the plasma, and compared the results obtained with those by Real Time PCR. Improving the reliability of T790M detection in cfDNA would represent a significant achievement, as it would permit the access to an effective therapeutic agent to a larger number of patients in the absence of repeated tissue biopsies. Variable T790M detection rates have been reported ranging between 31 and 66% for BEAMing (beads, emulsion, amplification and magnetics) digital PCR 18–52% for droplet digital PCR (ddPCR) and 22–30% for common Real Time PCR assays (Luo et al. The current methods for the detection of plasma T790M in clinical practice include digital PCR (dPCR) techniques, Real Time PCR assays and Next Generation Sequencing (NGS) (Thress et al., 2015a Bartels et al. Because circulating cell-free tumor-derived DNA (ctDNA) is diluted out with normal DNA, ctDNA analysis is technically challenging requiring both sensitivity and accuracy (Murtaza et al. This approach is non-invasive, does not pose limitations to repeated sampling, and provides a sufficiently accurate assessment of intra and inter-tumor heterogeneity (Sundaresan et al. The cfDNA is becoming a reliable alternative source to tumor DNA, although the sensitivity of methods using cfDNA is generally lower (Ramalingam et al. Several studies have demonstrated the feasibility of assessing EGFR mutational status on circulating cell-free DNA (cfDNA) from plasma (Douillard et al. 2017).Īlthough T790M can be identified through a new biopsy of the progressing neoplasm, this procedure may be challenging as well as stressful for the patient, and could potentially lead to complications. Food and Drug Administration (FDA) has approved the use of osimertinib also in first line for advanced NSCLC harboring common EGFR mutations (Mok et al. Osimertinib is a third-generation EGFR TKI, designed to overcome resistance due to T790M and representing the current standard treatment for advanced, T790M-positive NSCLC patients progressing after first or second- generation EGFR TKI (Cross et al. EGFR T790M substitution has been indicated as the prevalent molecular event involved and occurs in approximately 50–60% of the cases developing TKI resistance (Yu et al. Most patients respond to first and second-generation EGFR TKIs, such as gefitinib, erlotinib and afatinib, but acquired resistance is likely to occur, leading to disease progression. 2009) that allowed identification of patients eligible for treatment with an EGFR tyrosine kinase inhibitor (TKI) (Singh & Jadhav 2018). The current standard work-up of Non Small Cell Lung Cancer (NSCLC) patients includes the search for sensitizing mutations of EGFR gene (Sharma et al. ![]() Tag-based NGS represents an accurate and sensitive tool in a clinical setting for non-invasive assessment and monitoring of T790M variant in NSCLC patients. Patients in whom the T790M mutation was detected in plasma, achieved an objective response to osimertinib (9/14, 64.28%). Moreover, the tag-based NGS identified EGFR activating mutations more efficiently than Real Time PCR (85.7% versus 61.9% detection rate, respectively), particularly of the L858R variant type (0.06–0.75 mutation abundance range). ResultsĬompared to Real Time PCR, tag-based NGS improved the T790M detection rate (42.85% versus 21.4%, respectively), especially in those cases with a low median mutation abundance (i.e. MethodsĪ tag-based next generation sequencing (NGS) platform capable of tagging rare circulating tumor DNA alleles was employed in this study for the identification of T790M mutation in 42 post-TKI NSCLC patients. Improving sensitivity of T790M mutation detection in plasma ctDNA enables a larger number of NSCLC patients to receive the appropriate therapy without any further invasive procedure. Since circulating tumor DNA (ctDNA) is present in very low amounts in plasma, high sensitive and specific methods are required for molecular analysis. The demonstration of EGFR T790M gene mutation in plasma is crucial to assess the eligibility of Non Small Cell Lung Cancer (NSCLC) patients, who have acquired resistance to first or second generation Tyrosine Kinase Inhibitors (TKIs), to receive a subsequent treatment with osimertinib.
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